Purpose: The serotonin receptor subtype 2A antagonist (5-HT_2AR) (R)-[¹⁸F]MH.MZ has in preclinical studies been identified as a promising PET imaging agent for quantification of cerebral 5-HT_2ARs. It displays a very similar selectivity profile as [¹¹C]MDL 100907, one of the most selective compounds identified thus far for the 5-HT_2AR. As [¹¹C]MDL 100907, (R)-[¹⁸F]MH.MZ also displays slow brain kinetics in various animal models; however, the half-life of fluorine-18 allows for long scan times and consequently, a more precise determination of 5-HT_2AR binding could still be feasible. In this study, we aimed to evaluate the potential of (R)-[¹⁸F]MH.MZ PET to image and quantify the 5-HT_2AR in the human brain in vivo. Methods: Nine healthy volunteers underwent (R)-[¹⁸F]MH.MZ PET at baseline and four out of these also received a second PET scan, after ketanserin pretreatment. Regional time–activity curves of 17 brain regions were analyzed before and after pretreatment. We also investigated radiometabolism, time-dependent stability of outcomes measures, specificity of (R)-[¹⁸F]MH.MZ 5-HT_2AR binding, and performance of different kinetic modeling approaches. Results: Highest uptake was determined in 5-HT_2AR rich regions with a BP_ND of approximately 1.5 in cortex regions. No radiometabolism was observed. 1TCM and 2TCM resulted in similar outcome measure, whereas reference tissue models resulted in a small, but predictable bias. (R)-[¹⁸F]MH.MZ binding conformed to the known distribution of 5-HT_2AR and could be blocked by pretreatment with ketanserin. Moreover, outcomes measures were stable after 100–110 min. Conclusion: (R)-[¹⁸F]MH.MZ is a suitable PET tracer to image and quantify the 5-HT_2AR system in humans. In comparison with [¹¹C]MDL 100907, faster and more precise outcome measure could be obtained using (R)-[¹⁸F]MH.MZ. We believe that (R)-[¹⁸F]MH.MZ has the potential to become the antagonist radiotracer of choice to investigate the human 5-HT_2AR system.